Alpha-oxoacyl amino-caprolactam body

ABSTRACT

The purpose of the present invention is to provide a pharmaceutical composition that is useful for the treatment of diseases that are caused by an increase in bone resorption and that does not cause serious side effects even when used in combination with another drug. The present invention relates to: an α-oxoacyl amino-caprolactam that is represented by formula (I) 
     
       
         
         
             
             
         
       
     
     (in formula (I), X represents N or CH, Y represents O or CH 2 , and Z represents S or CH 2 ); and a bone resorption inhibitor containing the α-oxoacyl amino-caprolactam.

TECHNICAL FIELD

The present invention relates to a novel α-oxoacylaminocaprolactam. Specifically, the present invention relates to an α-oxoacylaminocaprolactam having the effect of selectively inhibiting cathepsin K, which is the principal cysteine protease particularly involved in bone resorption.

BACKGROUND ART

In recent years, as the aging society rapidly develops, the number of patients with senile diseases, particularly, the number of patients with bone diseases has been steadily increasing. Among them, osteoporosis is a serious problem, which often occurs in women, particularly, postmenopausal women. The accelerated bone resorption caused by the hormone imbalance or the aging process in postmenopausal women is closely involved in the development and progression of bone diseases. Therefore, bone resorption inhibitors are generally used in drug therapy for osteoporosis. However, bone resorption-inhibiting drugs being used currently, such as calcitonin preparations, estrogen preparations, vitamin K preparations, and bisphosphonate preparations, have problems with their therapeutic efficacy, immediate effectivity, side effects, dose compliance, or the like, and there has been a demand for the development of bone resorption inhibitors having the potential to become more effective drugs for treating or preventing osteoporosis.

In the living body, equilibrium is maintained between the concentrations of calcium in the bone and in the blood, and calcium constantly moves between the bone and the blood. Such movement of calcium between the bone and the blood is managed by the dynamic turnover between bone formation and bone resorption. It is known that in the bone resorption process, activated osteoclasts dissolve bone minerals such as calcium while the cysteine proteases released from the osteoclasts decompose the organic components of the bone, such as collagen, so that bone resorption is accelerated. Cysteine proteases such as cathepsins B, H, L, and S are present in the lysosomes of osteoclasts. In 1995, human cathepsin K localized in osteoclasts was isolated and found to be produced more in osteoclasts than other cathepsins (see Non Patent Literatures 1 and 2). It was also found that dwarfism patients with abnormal bone resorption have a mutation of the cathepsin K gene (see Non Patent Literature 3).

Thus, cathepsin K has attracted attention as the principal cysteine protease involved in bone resorption, and cathepsin K inhibitors are increasingly expected as bone resorption inhibitors. Aldehyde derivatives, epoxysuccinic acid derivatives (see Non Patent Literatures 4 and 5), or vinylsulfonic acid derivatives (see Non Patent Literatures 6 and 7) have been previously reported as cathepsin K-inhibiting compounds. Unfortunately, these derivatives are known to have low selectivity and to inhibit not only cathepsin K but also other cysteine proteases strongly (see Non Patent Literatures 8 to 10).

As cathepsin K has attracted attention as mentioned above, studies such as X-ray crystallography of cathepsin K and inhibitors have been actively conducted (see Non Patent Literatures 6 and 11), and some compounds are currently known to have the effect of selectively inhibiting cathepsin K (see Patent Literatures 1 to 4 and Non Patent Literatures 12 to 15).

Cytochrome P450 (hereinafter also referred to as CYP) is a typical enzyme involved in drug metabolism. In particular, CYP3A4 is a molecular species involved in the metabolism of at least 50% of the drugs being clinically used at present. The presence of a drug capable of inhibiting a drug metabolism enzyme may incur the risk of causing or enhancing side effects by preventing the enzyme from metabolizing another drug used in combination and increasing the blood concentration of the drug used in combination (see Non Patent Literatures 16 and 17). At present, therefore, checking for CYP3A4 inhibitory activity is generally performed at the initial stage of drug development studies, and inhibitory compounds are generally excluded from candidate compounds (see Non Patent Literature 17). In particular, it is considered that drugs for treating osteoporosis must have low CYP3A4 inhibitory activity because elderly people, who are to be given the drugs, often take a combination of drugs and often have decreased drug metabolism.

IC₅₀ values (50% inhibitory concentrations) are generally used to determine the intensity of the CYP inhibitory activity. In general, the intensity is classified as a high level when IC₅₀<1 μM, a medium level when 1 μM<IC₅₀<10 μM, and a low level when IC₅₀>10 μM (see Non Patent Literatures 18 and 19). Therefore, compounds with an IC₅₀ of more than 10 μM as the intensity of CYP3A4 inhibitory activity must be selected for drugs for chronic diseases of elderly people.

CITATION LIST Patent Literatures

-   Patent Literature 1: JP 2000-204071 A -   Patent Literature 2: WO 98/01133 -   Patent Literature 3: WO 01/58886 -   Patent Literature 4: WO 03/075836

Non Patent Literatures

-   Non Patent Literature 1: Biochem. Biophys. Res. Commun., 206, p 89     (1995) -   Non Patent Literature 2: J. Biol. Chem., 271, p 12511 (1996) -   Non Patent Literature 3: Science, 273, p 1236 (1996) -   Non Patent Literature 4: J. Biol. Chem., 271, p 2126 (1996) -   Non Patent Literature 5: Biol. Pharm. Bull., 19, p 1026 (1996) -   Non Patent Literature 6: Nature Structural Biology, 4, p 105 (1997) -   Non Patent Literature 7: J. Med. Chem., 38, p 3193 (1995) -   Non Patent Literature 8: Enzyme Inhibition, 3, p 13 (1989) -   Non Patent Literature 9: Biochem. Biophys. Res. Commun., 153, p 1201     (1988) -   Non Patent Literature 10: J. Biochem., 88, p 1805 (1980) -   Non Patent Literature 11: Nature Structural Biology, 4, p 109 (1997) -   Non Patent Literature 12: Proc. Natl. Acad. Sci. USA., 94, p 14249     (1997) -   Non Patent Literature 13: J. Am. Chem. Soc., 120, p 9114 (1998) -   Non Patent Literature 14: J. Med. Chem., 41, p 3563 (1998) -   Non Patent Literature 15: Bioorg. Med. Chem. Lett., 14, p 4897     (2004) -   Non Patent Literature 16: Rinsho Yakubutsu Dotaigaku (Clinical     Pharmacokinetics) (revised 4th edition), Nankodo Co., Ltd., p 71-85,     p 173-228 (2009) -   Non Patent Literature 17: Nichiyakurishi (Folia Pharmacol. Jpn.),     134, p 285-288 (2009) -   Non Patent Literature 18: Phytomedicine. 2011 Apr. 15; 18(6): p     533-8 -   Non Patent Literature 19: Annu. Rev. Pharmacol. Toxicol. 2000; 40: p     133-57

SUMMARY OF INVENTION Technical Problem

The present invention provides a novel compound that has cathepsin K inhibitory activity but has substantially no CYP3A4 inhibitory activity. More specifically, the present invention provides a bone resorption inhibitor having substantially no CYP3A4 inhibitory activity and a pharmaceutical composition useful for preventing and/or treating diseases caused by accelerated bone resorption, such as osteoporosis.

More specifically, the present invention provides a novel compound that has extremely low CYP3A4 inhibitory activity and is highly effective not only in inhibiting cathepsin K in vitro but also in inhibiting bone resorption in vivo; a bone resorption inhibitor including such a novel compound; and a pharmaceutical composition useful for preventing and/or treating diseases caused by accelerated bone resorption, such as osteoporosis.

Solution to Problem

So far, the inventors have developed a large number of cathepsin K-inhibiting compounds and tried to put them into practical use as drugs for treating metabolic bone diseases. Unfortunately, these compounds have been found to have high CYP3A4 inhibitory activity and have not been put into practical use yet. Thus, the inventors have actively searched for compounds that have cathepsin K inhibitory activity but have no CYP3A4 inhibitory activity. As a result, the inventors have surprisingly found that α-oxoacylaminocaprolactam derivatives, more specifically, compounds of formula (I) shown below exhibit almost no CYP3A4 inhibition and have high cathepsin K inhibitory activity, and have accomplished the present invention based on these findings.

Specifically, the present invention is directed to a novel α-oxoacylaminocaprolactam derivative and a pharmaceutical composition, specifically a bone resorption inhibitor, including the derivative as an active ingredient.

More specifically, the present invention is directed to items [1] to [14] below.

[1] An α-oxoacylaminocaprolactam of formula (I):

wherein X is N or CH, Y is O or CH₂, and Z is S or CH₂. [2] The α-oxoacylaminocaprolactam according to item [1], wherein in formula (I), X is N, Y is CH₂, and Z is S. [3] The α-oxoacylaminocaprolactam according to item [1], wherein in formula (I), X is N, Y is CH₂, and Z is CH₂. [4] The α-oxoacylaminocaprolactam according to item [1], wherein in formula (I), X is CH, Y is O, and Z is CH₂. [5] A bone resorption inhibitor including the α-oxoacylaminocaprolactam according to any one of items [1] to [4]. [6] A pharmaceutical composition including the α-oxoacylaminocaprolactam according to any one of items [1] to [4] and a pharmaceutically acceptable carrier. [7] The pharmaceutical composition according to item [6], which is a medicament for treating or preventing a disease caused by accelerated bone resorption. [8] The pharmaceutical composition according to item [7], wherein the disease caused by accelerated bone resorption is osteoporosis, hypercalcemia, Paget's disease, bone resorption disease, osteogenesis imperfecta, osteoarthritis, rheumatoid arthritis, arthritis, Klinefelter syndrome, hereditary hyperphosphatasia, Charcot neuroarthropathy, mastocytosis, Gaucher disease, cancer metastasis, or multiple myeloma. [9] A method of treating a disease caused by accelerated bone resorption, including administering an effective amount of the α-oxoacylaminocaprolactam according to any one of items [1] to [4] to a patient with a disease caused by accelerated bone resorption. [10] The method according to item [9], wherein the disease caused by accelerated bone resorption is osteoporosis, hypercalcemia, Paget's disease, bone resorption disease, osteogenesis imperfecta, osteoarthritis, rheumatoid arthritis, arthritis, Klinefelter syndrome, hereditary hyperphosphatasia, Charcot neuroarthropathy, mastocytosis, Gaucher disease, cancer metastasis, or multiple myeloma. [11] The α-oxoacylaminocaprolactam according to any one of items [1] to [4], which is for use in a method of treating or preventing a disease caused by accelerated bone resorption. [12] The α-oxoacylaminocaprolactam according to item [11], wherein the disease caused by accelerated bone resorption is osteoporosis, hypercalcemia, Paget's disease, bone resorption disease, osteogenesis imperfecta, osteoarthritis, rheumatoid arthritis, arthritis, Klinefelter syndrome, hereditary hyperphosphatasia, Charcot neuroarthropathy, mastocytosis, Gaucher disease, cancer metastasis, or multiple myeloma. [13] Use of the α-oxoacylaminocaprolactam according any one of items [1] to [4] for the manufacture of a pharmaceutical composition for treating or preventing a disease caused by accelerated bone resorption. [14] The use according to item [13], wherein the disease caused by accelerated bone resorption is osteoporosis, hypercalcemia, Paget's disease, bone resorption disease, osteogenesis imperfecta, osteoarthritis, rheumatoid arthritis, arthritis, Klinefelter syndrome, hereditary hyperphosphatasia, Charcot neuroarthropathy, mastocytosis, Gaucher disease, cancer metastasis, or multiple myeloma.

Advantageous Effects of Invention

The α-oxoacylaminocaprolactam of formula (I) of the present invention, which has high cathepsin K inhibitory activity with only a low level of CYP3A4 inhibitory activity, can be used as an active ingredient in a pharmaceutical composition for preventing and/or treating diseases that can be ameliorated by inhibiting substantial bone resorption (such as osteoporosis, hypercalcemia, Paget's disease, bone resorption disease, osteogenesis imperfecta, osteoarthritis, rheumatoid arthritis, arthritis, Klinefelter syndrome, hereditary hyperphosphatasia, Charcot neuroarthropathy, mastocytosis, Gaucher disease, cancer metastasis, and multiple myeloma). The compound of the present invention has not only cathepsin K inhibitory activity in vitro but also high bone resorption inhibitory activity in vivo.

The α-oxoacylaminocaprolactam of formula (I) of the present invention, which only has a low level of CYP3A4 inhibitory activity, is less likely to cause serious side-effects even when used in combination with other drugs. Therefore, the α-oxoacylaminocaprolactam of formula (I) of the present invention can be safely administered to elderly people who suffer from different diseases and take many drugs in combination.

Therefore, the present invention provides a pharmaceutical composition for preventing and/or treating diseases caused by accelerated bone resorption, which includes, as an active ingredient, a safe, practical, orally-administrable compound that has bone resorption inhibitory activity and is less likely to cause serious side-effects even when used in combination with other drugs.

DESCRIPTION OF EMBODIMENTS

The α-oxoacylaminocaprolactam of the present invention is a compound of formula (I) shown above. In each molecule of the compound of formula (I) of the present invention, any of the hydrogen atoms may be replaced by deuterium or tritium atoms.

The α-oxoacylaminocaprolactam of formula (I) of the present invention is characterized in that it has a caprolactam (ε-lactam) group at the end, a nitrogen atom is bonded in the α-position relative to the caprolactam group, the steric configuration at the α-position is the S configuration, it has an isopropyl group at the center, the steric configuration of the carbon atom bonded to the isopropyl group is also the S configuration, and it has a 1-amino-cyclohexanecarboxylic acid structure. The α-oxoacylaminocaprolactam of formula (I) of the present invention is further characterized by having a five-membered heterocyclic skeleton, preferably a thiazoline skeleton, a pyrrolidine skeleton, or a tetrahydrofuran skeleton, at the end.

The α-oxoacylaminocaprolactam of the present invention is further characterized in that it has almost no CYP3A4 inhibitory activity but has cathepsin K inhibitory activity, which is its specific property.

The α-oxoacylaminocaprolactam derivative of the present invention and the compound described in Patent Literature 1 are different compounds because the α-oxoacylaminocaprolactam derivative of the present invention differs in the R¹ moiety of the compound described in Patent Literature 1. Specifically, Patent Literature 1 states that R¹ may be a substituted amide group, and also states that the substituted amide group refers to a group represented by the formula R⁹—CONH— and having any of various substituents on the carbon atom of the amide bond group, in which the substituent R⁹ on the carbon atom may be the substituted or unsubstituted alkyl group, substituted alkoxy, phenoxy, 1-naphthyloxy, 2-naphthyloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted amino, substituted or unsubstituted aromatic hydrocarbon, or substituted or unsubstituted heterocycle (Patent Literature 1, claim 6). Patent Literature 1 only discloses that the heterocyclic group for R⁹ in the compound is specifically a six-membered ring (morpholine, substituted piperidine, thiomorpholine, substituted piperazine), a seven-membered ring (substituted homopiperazine), or a condensed ring (1,3-benzodioxole). In addition, Patent Literature 1 does not disclose any combination of such a heterocyclic amide group and caprolactam (ε-lactam) or the like.

Therefore, Patent Literature 1 does not suggest any five-membered heterocyclic group or any thiazolidine, pyrrolidine, or tetrahydrofuran ring for the present invention, and does not teach anything about their effectiveness.

It is apparent from the above that Patent Literature 1 discloses nothing about compound examples or related data suggestible for the accomplishment of the present invention.

In formula (I) representing the compound of the present invention, X is N or CH, Y is O or CH₂, and Z is S or CH₂. Any possible combination thereof may be employed for X, Y, and Z. Preferred combinations include a combination of N for X, CH₂ for Y, and S for Z; a combination of N for X, CH₂ for Y, and CH₂ for Z; and a combination of CH for X, O for Y, and CH₂ for Z.

The α-oxoacylaminocaprolactam of formula (I) of the present invention encompasses not only an α-oxoacylaminocaprolactam of formula (I) but also a pharmaceutically acceptable salt thereof, any of various hydrates and solvates thereof, any of crystal polymorphisms thereof, a deuterated derivative thereof, a tritiated derivative thereof, or the like.

Solvates of the α-oxoacylaminocaprolactam of formula (I) of the present invention include hydrates and various solvates (e.g., solvates with water or an alcohol such as ethanol).

The α-oxoacylaminocaprolactam of formula (I) of the present invention can be produced by an appropriate combination of known chemical synthesis techniques. For example, the α-oxoacylaminocaprolactam of formula (I) can be produced by the method shown below or a method similar thereto.

In the formulae, R is an ester residue, Boc is a tert-butoxycarbonyl group, and X, Y, and Z are the same as defined above.

First Process

This process may include producing an isocyanate of formula (III) from an aminocyclohexanecarboxylic acid ester derivative of formula (II) and then allowing the isocyanate of formula (III) to react with thiazolidine to produce an amidocyclohexanecarboxylic acid ester derivative of formula (IV).

This process may be a process of allowing the aminocyclohexanecarboxylic acid ester derivative of formula (II) to react with a heterocyclic carboxylic acid derivative to produce the amidocyclohexanecarboxylic acid ester derivative of formula (IV) directly (hereinafter referred to as “process 1-A”) or a process that includes converting the aminocyclohexanecarboxylic acid ester derivative of formula (II) to the isocyanate of formula (III) and then allowing the isocyanate of formula (III) to react with a nitrogen atom-containing heterocyclic compound such as thiazolidine or pyrrolidine to produce the amidocyclohexanecarboxylic acid ester derivative of formula (IV) (hereinafter referred to as “process 1-B”).

Process 1-A

This process may include condensing the aminocyclohexanecarboxylic acid ester derivative of formula (II) with tetrahydro-2-furancarboxylic acid to produce the amidocyclohexanecarboxylic acid ester derivative of formula (IV).

In this process, a condensing agent may be used, such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, diisopropylcarbodiimide, or carbonyldiimidazole. In this process, if necessary, an activating agent may also be added, such as 1-hydroxybenzotriazole or N-hydroxysuccinimide.

Alternatively, in this process, the condensation may be performed by a mixed acid anhydride method using an acid halide in the presence of a base. The acid halide for use in this process may be, for example, pivaloyl chloride, isobutyl chloroformate, methyl chloroformate, ethyl chloroformate, methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, or the like. The base may be, for example, pyridine, triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, N-methylmorpholine, N,N-dicyclohexylamine, or the like.

This process is preferably performed in a solvent such as methylene chloride, chloroform, dichloroethane, ethyl acetate, acetone, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, or dimethoxyethane.

The reaction temperature is generally in the range of −30° C. to 200° C., preferably in the range of 0° C. to 100° C.

Process 1-B

The process of producing the isocyanate (III) from the aminocyclohexanecarboxylic acid ester derivative of formula (II) may be performed by a method using di-tert-butyl dicarbonate and 4-(dimethylamino)pyridine or a method using phosgene or triphosgene. In this process, if necessary, a base may be added, such as pyridine, triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, N-methylmorpholine, or N,N-dicyclohexylamine. This process is preferably performed in a solvent such as dichloromethane, chloroform, dichloroethane, ethyl acetate, acetone, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, or dimethoxyethane.

The reaction temperature is generally in the range of −30° C. to 200° C., preferably in the range of 0° C. to 100° C.

The process of producing the amidocyclohexanecarboxylic acid ester derivative of formula (IV) by reaction of the isocyanate of formula (III) with thiazolidine or pyrrolidine may be performed without any solvent or in a solvent. The solvent may be, for example, chloroform, dichloroethane, ethyl acetate, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, or the like. In this process, a base may also be added, such as pyridine, triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, N-methylmorpholine, or N,N-dicyclohexylamine. The base may be added in an amount in the range of a catalytic amount to an excess amount.

The reaction temperature may be in the range of −20° C. to 300° C., preferably in the range of 0° C. to 100° C.

The aminocyclohexanecarboxylic acid ester derivative of formula (II) may be a C1 to C6 linear or branched alkyl ester, preferably a C1 to C4 linear or branched alkyl ester; a C7 to C15 arylalkyl ester, preferably a C7 to C12 arylalkyl ester, or the like. Examples include 1-aminocyclohexanecarboxylic acid methyl ester, 1-aminocyclohexanecarboxylic acid ethyl ester, 1-aminocyclohexanecarboxylic acid n-propyl ester, 1-aminocyclohexanecarboxylic acid 2-propyl ester, 1-aminocyclohexanecarboxylic acid n-butyl ester, 1-aminocyclohexanecarboxylic acid 2-methylpropyl ester, 1-aminocyclohexanecarboxylic acid 1,1-dimethylethyl ester, 1-aminocyclohexanecarboxylic acid benzyl ester, and the like.

The amidocyclohexanecarboxylic acid ester derivative of formula (IV) may be, for example, 1-[[(3-thiazolidinylcarbonyl)]amino]cyclohexanecarboxylic acid methyl ester, 1-[[(3-thiazolidinylcarbonyl)]amino]cyclohexanecarboxylic acid ethyl ester, 1-[[(3-thiazolidinylcarbonyl)]amino]cyclohexanecarboxylic acid n-propyl ester, 1-[[(3-thiazolidinylcarbonyl)]amino]cyclohexanecarboxylic acid 2-propyl ester, 1-[[(3-thiazolidinylcarbonyl)]amino]cyclohexanecarboxylic acid n-butyl ester, 1-[[(3-thiazolidinylcarbonyl)]amino]cyclohexanecarboxylic acid 2-methylpropyl ester, 1-[[(3-thiazolidinylcarbonyl)]amino]cyclohexanecarboxylic acid 1,1-dimethylethyl ester, 1-[[(3-thiazolidinylcarbonyl)]amino]cyclohexanecarboxylic acid benzyl ester;

1-[(1-pyrrolidinylcarbonyl)amino]cyclohexanecarboxylic acid methyl ester, 1-[(1-pyrrolidinylcarbonyl)amino]cyclohexanecarboxylic acid ethyl ester, 1-[(1-pyrrolidinylcarbonyl)amino]cyclohexanecarboxylic acid n-propyl ester, 1-[(1-pyrrolidinylcarbonyl)amino]cyclohexanecarboxylic acid 2-propyl ester, 1-[(1-pyrrolidinylcarbonyl)amino]cyclohexanecarboxylic acid n-butyl ester, 1-[(1-pyrrolidinylcarbonyl)amino]cyclohexanecarboxylic acid 2-methylpropyl ester, 1-[(1-pyrrolidinylcarbonyl)amino]cyclohexanecarboxylic acid 1,1-dimethylethyl ester, 1-[(1-pyrrolidinylcarbonyl)amino]cyclohexanecarboxylic acid benzyl ester;

1-[[[(2S)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid methyl ester, 1-[[[(2S)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid ethyl ester, 1-[[[(2S)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid n-propyl ester, 1-[[[(2S)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid 2-propyl ester, 1-[[[(2S)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid n-butyl ester, 1-[[[(2S)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid 2-methylpropyl ester, 1-[[[(2S)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid 1,1-dimethylethyl ester, 1-[[[(2S)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid benzyl ester, 1-[[[(2R)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid methyl ester, 1-[[[(2R)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid ethyl ester, 1-[[[(2R)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid n-propyl ester, 1-[[[(2R)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid 2-propyl ester, 1-[[[(2R)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid n-butyl ester, 1-[[[(2R)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid 2-methylpropyl ester, 1-[[[(2R)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid 1,1-dimethylethyl ester, 1-[[[(2R)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid benzyl ester; and the like.

Second Process

This process includes subjecting the amidocyclohexanecarboxylic acid ester derivative of formula (IV) (produced in the first process) to a hydrolysis reaction or a hydrogenation reaction using a metal catalyst for catalytic reduction to produce an amidocyclohexanecarboxylic acid of formula (V).

The hydrolysis reaction may be performed in the presence of an acid or a base. The acid may be, for example, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or the like. The base may be, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, or the like. This process is preferably performed in water or a mixed solvent of water and an organic solvent such as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, tetrahydrofuran, or dimethoxyethane. The reaction temperature is generally in the range of −20° C. to 200° C., preferably in the range of 0° C. to 180° C.

When the oxyamidocyclohexanecarboxylic acid ester derivative of formula (IV) is a benzyl ester (R is benzyl), the oxyamidocyclohexanecarboxylic acid of formula (V) can be produced by a hydrogenation reaction using a metal catalyst for catalytic reduction. The metal catalyst for the production by the catalytic hydrogenation reaction may be, for example, a platinum catalyst such as PtO₂ or Pt/C, a palladium catalyst such as Pd/C, Pd/BaSO₄, Pd/CaCO₃, Pd/SrCO₃, Pd black, PdO, or Pd(OH)₂, a nickel catalyst such as Raney nickel, a rhodium catalyst such as Rh/C, Rh/Al₂O₃, RhCl(PPh₃)₃, RhH(CO)(PPh₃)₃, or Rh(OCOCH₃)₄, a ruthenium catalyst such as RuO₂, Ru/C, Ru(OCOMe)(PPh₃)₃, or Ru(OCOCF₃)(PPh₃)₃, a copper catalyst such as Cu—CrO or Cu—Ba—CrO, or the like.

This process is preferably performed in a solvent such as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, diisopropyl ether, tetrahydrofuran, benzene, toluene, xylene, dimethylformamide, dioxane, or water. The reaction temperature is generally in the range of −50° C. to 200° C., preferably in the range of 10° C. to 100° C.

Third Process

This process includes oxidizing tert-butoxycarbonyl-L-valinol of formula (VI) to produce tert-butoxycarbonyl-L-valinal of formula (VII).

In this process, the oxidation reaction may be activated DMSO (dimethyl sulfoxide) oxidation. In this reaction, an electrophilic activating reagent may be used, such as dicyclohexylcarbodiimide, phosphorus pentoxide, a pyridine-sulfur trioxide complex, acetic anhydride, mercury (II) acetate, or oxalyl chloride. In this process, if necessary, a hydrogen donor may also be added, such as phosphoric acid, trifluoroacetic acid, dichloroacetic acid, pyridine-phosphoric acid, or pyridine-trifluoroacetic acid. If necessary, an amine may also be added, such as triethylamine, N,N-diisopropylethylamine, or N-methylmorpholine.

This process may be performed in dimethyl sulfoxide, and if necessary, a solvent may also be added, such as dichloromethane, chloroform, dichloroethane, toluene, acetone, or tetrahydrofuran.

The reaction temperature is generally in the range of −80° C. to 200° C., preferably in the range of −40° C. to 40° C.

Alternatively, in this process, an active species with a structure similar to that for the activated DMSO reaction may be prepared from a sulfide and a halogen for the oxidation reaction.

In this process, the sulfide may be, for example, dimethyl sulfide, methyl phenyl sulfide, or the like. The halogenating agent may be, for example, N-chlorosuccinimide, chlorine, or the like.

In this process, if necessary, an amine may also be added, such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, or 1,8-diazabicyclo[5.4.0]undec-7-en (DBU).

This process is preferably performed in a solvent such as dichloromethane, chloroform, dichloroethane, toluene, or tetrahydrofuran.

The reaction temperature is generally in the range of −80° C. to 200° C., preferably in the range of −40° C. to 40° C.

Alternatively, in this process, the oxidation may be performed using a high-valence iodine compound reagent.

In this process, the high-valence iodine compound may be, for example, a Dess-Martin reagent (1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one), IBX (1-hydroxy-1,2-benziodoxol-3-(1H)-1-oxide), or the like.

In this process, if necessary, a base may also be added, such as pyridine or sodium hydrogen carbonate.

This process is preferably performed in a solvent such as dichloromethane, chloroform, dichloroethane, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, or dimethoxyethane.

The reaction temperature may be in the range of −20° C. to 200° C., preferably in the range of 0° C. to 40° C.

Alternatively, in this process, the oxidation may be performed using an aluminum alkoxide and a hydrogen acceptor (Oppenauer oxidation). The aluminum alkoxide may be, for example, aluminum isopropoxide or aluminum tert-butoxide.

The hydrogen acceptor may be, for example, benzoquinone, benzophenone, acetone, cyclohexanone, benzaldehyde, or the like.

This process is preferably performed in a solvent such as benzene, toluene, or xylene.

The reaction temperature may be in the range of −20° C. to 200° C., preferably in the range of 0° C. to 150° C.

Alternatively, in this process, the oxidation reaction may be performed using tetrapropylammonium perruthenate (TPAP). N-methylmorpholine-N-oxide or molecular oxygen may be used as an oxidizing agent.

This process is preferably performed in a solvent such as dichloromethane, acetonitrile, or toluene. In this process, if necessary, molecular sieves 4A may be added.

The reaction temperature may be in the range of −20° C. to 200° C., preferably in the range of 0° C. to 40° C.

Alternatively, in this process, the oxidation reaction may be performed using 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) or a derivative thereof.

A hypochlorite is preferably used as an oxidizing agent. A bromite, N-chlorosuccinimide, or the like may also be used as an oxidizing agent.

This process is preferably performed in a solvent such as dimethyl sulfoxide, dimethylformamide, dichloromethane, acetonitrile, toluene, or ethyl acetate. In this process, if necessary, sodium bromide or water may also be added.

The reaction temperature may be in the range of −20° C. to 200° C., preferably in the range of 0° C. to 40° C.

Fourth Process

This process includes adding a cyano group to the tert-butoxycarbonyl-L-valinal of formula (VII) to produce a cyanohydrin of formula (VIII), then subjecting the cyanohydrin of formula (VIII) to a hydrolysis reaction, and performing tert-butoxycarbonylation again to produce a hydroxycarboxylic acid of formula (IX).

In this process, the reaction to produce the cyanohydrin of formula (VIII) from the tert-butoxycarbonyl-L-valinal of formula (VII) may be performed using acetone cyanhydrin, sodium cyanide, potassium cyanide, hydrogen cyanide, copper cyanide, trimethylsilyl cyanide, or the like. If necessary, a base may also be added, such as pyridine, triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, N-methylmorpholine, or N,N-dicyclohexylamine, or a Lewis acid may also be added, such as zinc chloride, titanium tetrachloride, titanium tetraisopropoxide, aluminum chloride, or zinc trifluoromethanesulfonate.

This process is preferably performed in a solvent such as dichloromethane, chloroform, dichloroethane, ethyl acetate, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, dimethylformamide, acetonitrile, tetrahydrofuran, or dioxane.

The reaction temperature may be in the range of −20° C. to 200° C., preferably in the range of 0° C. to 100° C.

In this process, the cyanohydrin of formula (VIII) may be subjected to an acid hydrolysis reaction using an acid such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid. This reaction is preferably performed in water or a mixed solvent of water and an organic solvent such as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, tetrahydrofuran, dioxane, or dimethoxyethane. The reaction temperature is generally in the range of −20° C. to 200° C., preferably in the range of 0° C. to 180° C.

In the acid hydrolysis reaction, the Boc group for the amino group can also be decomposed simultaneously. To protect the amino group, therefore, tert-butoxycarbonylation reaction is preferably performed.

In this process, the tert-butoxycarbonylation reaction may be performed again using di-tert-butyl dicarbonate, 2-(tert-butoxycarbonylthio)-4,6-dimethylpyrimidine, or the like. The reaction may be performed in the presence of a base. The base may be an organic base such as pyridine, triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, N-methylmorpholine, or N,N-dicyclohexylamine, or an inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydrogen carbonate, sodium carbonate, or potassium carbonate. This process is preferably performed in water or a mixed solvent of water and an organic solvent such as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, tetrahydrofuran, dioxane, ethyl acetate, diethyl ether, diisopropyl ether, or dimethoxyethane. The reaction temperature is generally in the range of −20° C. to 200° C., preferably in the range of −10° C. to 100° C.

Fifth Process

This process includes condensing the hydroxycarboxylic acid of formula (IX) with L-(−)-α-amino-ε-caprolactam, preferably in the presence of a condensing agent, and then deprotecting the product to produce an aminoalcohol of formula (X).

The condensing agent for use in this process may be, for example, dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, diisopropylcarbodiimide, carbonyldiimidazole, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM), 2-chloro-1-methylpyridinium iodide, or the like. In this process, if necessary, an activating agent may also be added, such as 1-hydroxybenzotriazole or N-hydroxysuccinimide.

Alternatively, in this process, the condensation may be performed by a mixed acid anhydride method using an acid halide in the presence of a base. The acid halide for use in this process may be, for example, pivaloyl chloride, isobutyl chloroformate, methyl chloroformate, ethyl chloroformate, methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, or the like. The base may be, for example, pyridine, triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, N-methylmorpholine, N,N-dicyclohexylamine, or the like.

This process is preferably performed in a solvent such as dichloromethane, chloroform, dichloroethane, ethyl acetate, acetone, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, or dimethoxyethane.

The reaction temperature is generally in the range of −30° C. to 200° C., preferably in the range of −10° C. to 100° C.

The subsequent deprotection reaction may be performed using an acid such as hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid. This reaction is preferably performed in a solvent such as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, tetrahydrofuran, dioxane, ethyl acetate, or dimethoxyethane.

Sixth Process

This process includes condensing the amidocyclohexanecarboxylic acid of formula (V) with the aminoalcohol of formula (X), preferably in the presence of a condensing agent, to produce an α-hydroxyacylaminocaprolactam of formula (XI).

The condensing agent for use in this process may be, for example, dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, diisopropylcarbodiimide, carbonyldiimidazole, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM), 2-chloro-1-methylpyridinium iodide, or the like. In this process, if necessary, an activating agent may also be added, such as 1-hydroxybenzotriazole or N-hydroxysuccinimide.

Alternatively, in this process, the condensation may be performed by a mixed acid anhydride method using an acid halide in the presence of a base. The acid halide for use in this process may be, for example, pivaloyl chloride, isobutyl chloroformate, methyl chloroformate, ethyl chloroformate, methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, or the like. The base may be, for example, pyridine, triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, N-methylmorpholine, N,N-dicyclohexylamine, or the like.

This process is preferably performed in a solvent such as dichloromethane, chloroform, dichloroethane, ethyl acetate, acetone, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, or dimethoxyethane.

The reaction temperature is generally in the range of −30° C. to 200° C., preferably in the range of −10° C. to 100° C.

Seventh Process

This process includes oxidizing the α-hydroxyacylaminocaprolactam of formula (XI) to produce the α-oxyacylaminocaprolactam of formula (I).

In this process, the oxidation reaction may be activated DMSO (dimethyl sulfoxide) oxidation. In this reaction, an electrophilic activating reagent may be used, such as dicyclohexylcarbodiimide, phosphorus pentoxide, a pyridine-sulfur trioxide complex, acetic anhydride, mercury(II) acetate, or oxalyl chloride. In this process, if necessary, a hydrogen donor may also be added, such as phosphoric acid, trifluoroacetic acid, dichloroacetic acid, pyridine-phosphoric acid, or pyridine-trifluoroacetic acid. If necessary, an amine may also be added, such as triethylamine, N,N-diisopropylethylamine, or N-methylmorpholine.

This process may be performed in dimethyl sulfoxide, and if necessary, a solvent may be added, such as dichloromethane, chloroform, dichloroethane, toluene, acetone, or tetrahydrofuran.

The reaction temperature is generally in the range of −80° C. to 200° C., preferably in the range of −40° C. to 40° C.

Alternatively, in this process, an active species with a structure similar to that for the activated DMSO reaction may be prepared from a sulfide and a halogen for the oxidation reaction.

In this process, the sulfide may be, for example, dimethyl sulfide, methyl phenyl sulfide, or the like. The halogenating agent may be, for example, N-chlorosuccinimide, chlorine, or the like.

In this process, if necessary, an amine may also be added, such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, or 1,8-diazabicyclo[5.4.0]undec-7-en (DBU).

This process is preferably performed in a solvent such as dichloromethane, chloroform, dichloroethane, toluene, or tetrahydrofuran.

The reaction temperature is generally in the range of −80° C. to 200° C., preferably in the range of −40° C. to 40° C.

Alternatively, in this process, the oxidation may be performed using a high-valence iodine compound reagent.

In this process, the high-valence iodine compound may be, for example, a Dess-Martin reagent (1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one), IBX (1-hydroxy-1,2-benziodoxol-3-(1H)-1-oxide), or the like.

In this process, if necessary, a base may also be added, such as pyridine or sodium hydrogen carbonate.

This process is preferably performed in a solvent such as dichloromethane, chloroform, dichloroethane, benzene, toluene, xylene, dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, or dimethoxyethane.

The reaction temperature may be in the range of −20° C. to 200° C., preferably in the range of 0° C. to 40° C.

Alternatively, in this process, the oxidation may be performed using an aluminum alkoxide and a hydrogen acceptor (Oppenauer oxidation). The aluminum alkoxide may be, for example, aluminum isopropoxide or aluminum tert-butoxide.

The hydrogen acceptor may be, for example, benzoquinone, benzophenone, acetone, cyclohexanone, benzaldehyde, or the like.

This process is preferably performed in a solvent such as benzene, toluene, or xylene.

The reaction temperature may be in the range of −20° C. to 200° C., preferably in the range of 0° C. to 150° C.

Alternatively, in this process, the oxidation reaction may be performed using tetrapropylammonium perruthenate (TPAP). N-methylmorpholine-N-oxide or molecular oxygen may be used as an oxidizing agent.

This process is preferably performed in a solvent such as dichloromethane, acetonitrile, or toluene. In this process, if necessary, molecular sieves 4A may be added.

The reaction temperature may be in the range of −20° C. to 200° C., preferably in the range of 0° C. to 40° C.

Alternatively, in this process, the oxidation reaction may be performed using 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) or a derivative thereof.

A hypochlorite is preferably used as an oxidizing agent. A bromite, N-chlorosuccinimide, or the like may also be used as an oxidizing agent.

This process is preferably performed in a solvent such as dimethyl sulfoxide, dimethylformamide, dichloromethane, acetonitrile, toluene, or ethyl acetate. In this process, if necessary, sodium bromide or water may also be added.

The reaction temperature may be in the range of −20° C. to 200° C., preferably in the range of 0° C. to 40° C.

If necessary, the intermediates and the α-oxoacylaminocaprolactam derivative of formula (I) of the present invention, produced by any of these processes, may be purified by any of various known purification methods such as recrystallization, distillation, and chromatography.

The test results described below show that in the evaluation of cathepsin K inhibitory activity and the evaluation of bone resorption inhibitory activity using male mice, the α-oxoacylaminocaprolactam derivative of formula (I) of the present invention has activity equal to or greater than that of the compounds (cyclic amides) in the group described in JP 2000-204071 A, which are known to have cathepsin K inhibitory activity. However, the compounds (cyclic amides) in the group described in JP 2000-204071 A have CYP3A4 inhibitory activity and cannot only have bone resorption inhibitory activity without CYP3A4 inhibitory activity.

In contrast, compounds according to the present invention all have bone resorption inhibitory activity with no CYP3A4 inhibitory activity, which means that the compound group of the present invention can only have the desired pharmacological activity without any CYP3A4 inhibitory activity which may cause side effects.

Although it is not clear why the compound of the present invention has bone resorption inhibitory activity with no CYP3A4 inhibitory activity, it is suggested that only compounds with an extremely limited structure can be free of CYP3A4 inhibitory activity.

As shown below, the compound of the present invention has selective and potent cathepsin K inhibitory activity and high bone resorption inhibitory activity in an animal model. In addition, the compound of the present invention can serve as a bone resorption inhibitor with less side effects even when used in combination with other drugs. Therefore, the compound of the present invention can be used as an active ingredient in pharmaceutical compositions for treating or preventing diseases caused by accelerated bone resorption. Diseases caused by accelerated bone resorption include osteoporosis, hypercalcemia, Paget's disease, bone resorption diseases, osteogenesis imperfecta, osteoarthritis, rheumatoid arthritis, arthritis, Klinefelter syndrome, hereditary hyperphosphatasia, Charcot neuroarthropathy, mastocytosis, Gaucher disease, cancer metastasis, multiple myeloma, and the like.

The bone resorption inhibitor of the present invention or the therapeutic agent of the present invention for diseases caused by accelerated bone resorption includes the α-oxoacylaminocaprolactam of formula (I) as an active ingredient and can be used as a pharmaceutical composition containing the active ingredient. In this case, the compound of the present invention is generally used together with a pharmaceutically acceptable carrier and/or diluent, although the compound of the present invention may be used alone.

The compound of the present invention may be administered by any method. A suitable preparation for the compound of the present invention may be selected as appropriate depending on the therapeutic purpose. For example, such a preparation may be any of an oral agent, an injection, a suppository, an inhalant, and the like. Pharmaceutical compositions suitable for these dosage forms can be produced using known preparation methods.

For example, when oral solid preparations are prepared, the compound of formula (I) may be mixed with a pharmaceutically acceptable excipient and optionally an additive such as a binder, a disintegrator, a lubricant, a colorant, a corrigent, or a flavoring agent, and then tablets, coated tables, granules, powders, capsules, or the like may be prepared from the mixture using conventional methods. The additives may be appropriately selected from those generally used in the art. Examples of the excipient include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicate, and the like. Examples of the binder include water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinylpyrrolidone, and the like. Examples of the disintegrator include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose, and the like. Examples of the lubricant include purified talc, stearates, borax, polyethylene glycol, and the like. Examples of the corrigent include sucrose, bitter orange peel, citric acid, tartaric acid, and the like.

When an oral liquid preparation is prepared, internal liquid, syrup, elixir, or the like may be prepared by mixing the compound of formula (I) with a corrigent, a buffer, a stabilizer, a flavoring agent, and the like using conventional methods. The corrigent may be any of those listed above. The buffer may be sodium citrate or the like, and the stabilizer may be gum tragacanth, gum arabic, gelatin, or the like.

When an injection is prepared, a hypodermic injection, an intramuscular injection, and an intravenous injection may be prepared by mixing the compound of formula (I) with a pH adjusting agent, a buffer, a stabilizer, an isotonizing agent, a local anesthetic, and the like using conventional methods. Example of the pH adjusting agent and the buffer include sodium citrate, sodium acetate, sodium phosphate, and the like. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid, and the like. Examples of the local anesthetic include procaine hydrochloride, lidocaine hydrochloride, and the like. Examples of the isotonizing agent include sodium chloride, glucose, and the like.

A suppository can be prepared by mixing the compound of formula (I) with a known suppository carrier, such as polyethylene glycol, lanolin, cacao butter, or fatty acid triglyceride, and optionally a surfactant (such as Tween (registered trademark)) and then forming the suppository using conventional methods.

Besides those listed above, other preferred preparations may be appropriately prepared using conventional methods.

In general, 1 mg to 1,000 mg of the compound of formula (I) of the present invention is preferably administered to an adult orally or parenterally once or in several divided doses per day, although the dosage of the compound of formula (I) depends on the age, weight, and condition of the subject, dosage form, dosage frequency, and the like.

Hereinafter, the present invention will be more specifically described with reference to examples. It will be understood that the production examples and the examples are not intended to limit the present invention at all.

EXAMPLES Production Example 1 Production of 1-[(3-thiazolidinylcarbonyl)amino]cyclohexanecarboxylic acid

(1) Production of 1-[(3-thiazolidinylcarbonyl)amino]cyclohexanecarboxylic acid benzyl ester

At room temperature, 4-dimethylaminopyridine (1.90 g, 15.6 mmol) was added to a dichloromethane solution of benzyl 1-aminocyclohexanecarboxylate (36.48 g, 156 mmol) and di-tert-butyl dicarbonate (32.24 g, 148 mmol) and stirred for 40 minutes. Triethylamine (44.0 mL, 315 mmol) and thiazolidine (13.5 mL, 171 mmol) were added to the reaction mixture and further stirred at room temperature for 19 hours. The solvent was removed from the resulting reaction mixture by distillation in vacuo. After ethyl acetate was added to the residue, the mixture was washed with a saturated sodium hydrogen carbonate aqueous solution and brine. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation in vacuo. The resulting solid was washed with diethyl ether to give 49.60 g (91%) of the title compound.

¹H-NMR (CDCl₃, δ):

1.26-1.34 (1H, m), 1.41-1.61 (2H, m), 1.62-1.67 (3H, m), 1.89 (2H, td, J=7 Hz, 2 Hz), 2.06 (2H, d, J=7 Hz), 3.03 (2H, t, J=3 Hz), 3.68 (2H, t, J=3 Hz), 4.46 (1H, s), 4.47 (2H, s), 5.16 (2H, s), 7.30-7.37 (5H, m)

Rf value: 0.63 (hexane:AcOEt=1:1)

(2) Production of 1-[(3-thiazolidinylcarbonyl)amino]cyclohexanecarboxylic acid

A 6 M sodium hydroxide aqueous solution (380.0 mL, 2.28 mol) was added to an ethanol suspension of 1-[(3-thiazolidinylcarbonyl)amino]cyclohexanecarboxylic acid benzyl ester (264.26 g, 0.76 mol) at room temperature and stirred at 60° C. for 2 hours. After the solvent was removed from the reaction mixture by distillation in vacuo, the residue was neutralized with concentrated hydrochloric acid under ice cooling. The precipitated solid was separated by filtration and then washed with water and diisopropyl ether. The resulting solid was dried in vacuo to give 190.24 g (97%) of the title compound as a colorless solid.

¹H-NMR (CD₃OD, δ):

1.33-1.38 (1H, m), 1.51-1.62 (5H, m), 1.83 (2H, dt, J=8 Hz, 2 Hz), 2.07 (2H, d, J=8 Hz), 3.03 (2H, d, J=3 Hz), 3.68 (2H, t, J=3 Hz), 1.98 (2H, s)

Rf value: 0.16 (hexane:AcOEt=1:1)

Production Example 2 Production of (2R,3S)-3-amino-N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methylpentanamide and (2S,3S)-3-amino-N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methylpentanamide

(1) Production of Boc-L-valinal

Di-tert-butyl dicarbonate (211.6 g, 0.97 mol) was gradually added to a dichloromethane solution of L-valinol (100.0 g, 0.97 mol). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. To the residue (crude Boc-L-valinol) were added N,N-diisopropylethylamine (51.7 g, 0.4 mol), 1 L of dry dimethyl sulfoxide, and 200 ml of dry dichloromethane. Under ice cooling, sulfur trioxide-pyridine (63.7 g, 0.4 mol) was gradually added to the liquid mixture and stirred at the same temperature for 1 hour. The reaction mixture was poured into ice-water and then extracted twice with ethyl acetate. The organic layer was washed with a 20% citric acid aqueous solution, a saturated sodium hydrogen carbonate aqueous solution, and brine. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation in vacuo, so that 179.3 g (92%) of the title compound was obtained.

¹H-NMR (CDCl₃, δ):

0.95 (3H, d, J=7 Hz), 1.04 (3H, d, J=7 Hz), 1.45 (9H, m), 2.24-2.34 (1H, m), 4.22-4.28 (1H, m), 5.08 (1H, br-s), 9.65 (1H, s)

(2) Production of (2RS,3S)-2-hydroxy-4-methyl-3-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoic acid

Under ice cooling, triethylamine (9.0 g, 89 mmol) was added dropwise to a dichloromethane solution of Boc-L-valinal (179.3 g, 881 mmol) and acetone cyanhydrin (310.6 g, 3.56 mol). The reaction mixture was returned to room temperature and then stirred overnight. The reaction mixture was concentrated in vacuo, and the residue was dissolved in 20% ethyl acetate/hexane. The solution was washed with water. The aqueous layer was extracted with 20% ethyl acetate/hexane, and the extract was combined with the organic layer. The organic layer was further washed with water, and the aqueous layer was extracted again with 20% ethyl acetate/hexane, and the extract was combined with the organic layer. After the combined organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation in vacuo. The residue (crude (2RS,3S)-2-hydroxy-4-methyl-3-[[(1,1-dimethylethoxy)carbonyl]amino]pentanenitrile) was dissolved in 500 ml of dioxane, and 500 ml of concentrated hydrochloric acid was added dropwise to the solution. The liquid mixture was refluxed for 2 hours and then returned to room temperature. The solvent was then removed by distillation in vacuo. After the residue was dissolved in water, 300 ml of triethylamine was added to the solution. The mixture was stirred at room temperature for 1 hour and then concentrated again in vacuo. The residue was dissolved in 400 ml of dioxane and 400 ml of water. After triethylamine (108.3 g, 1.07 mol) was added to the solution, di-tert-butyl dicarbonate (194.2 g, 0.89 mol) was added to the mixture and then stirred at room temperature overnight. The reaction mixture was concentrated. After the concentrate was dissolved in diethyl ether, the solution was extracted once with water and twice with 90 ml of a 1 M sodium hydroxide aqueous solution. Under ice cooling, 15 ml of concentrated hydrochloric acid was added to the combined aqueous layer. After returned to room temperature, the liquid mixture was acidified with potassium hydrogen sulfate and then extracted twice with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation in vacuo, so that 141.0 g (64%) of the title compound was obtained.

¹H-NMR (CDCl₃, δ):

0.99 (3H, d, J=7 Hz), 1.05 (3H, d, J=7 Hz), 1.42 (9/2H, s), 1.45 (9/2H, s), 2.01-2.16 (1H, m), 3.55-3.68 (1H, m), 4.39 (1/2H, d, J=2 Hz), 4.41 (1/2H, d, J=3 Hz), 4.86 (1/2H, d, J=7 Hz), 4.99 (1/2H, d, J=10 Hz)

(3) Production of (2R,3S)—N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methyl-3-[[(1,1-dimethylethoxy)carbonyl]amino]pentanamide and (4) production of (2S,3S)—N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methyl-3-[[(1,1-dimethylethoxy)carbonyl]amino]pentanamide

Under ice cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (120.2 g, 0.63 mol) was added to an N,N-dimethylformamide solution of (2RS,3S)-2-hydroxy-4-methyl-3-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoic acid (141.0 g, 0.57 mol), L-(−)-α-amino-ε-caprolactam (73.1 g, 0.57 mol), and 1-hydroxybenzotriazole (91.7 g, 0.60 mol). The reaction mixture was returned to room temperature, stirred overnight, and then poured into a 1:1 aqueous solution of a saturated sodium hydrogen carbonate aqueous solution and water. The precipitated crystals were separated by filtration and then washed with water. The filtrate was extracted with chloroform, and the organic layer was washed with a 10% potassium hydrogen sulfate aqueous solution, saturated sodium bicarbonate water, and brine, and then dried over sodium sulfate. The solvent was removed by distillation in vacuo. Ethyl acetate was added to the residue and stirred for 4 hours. The precipitated crystals were separated by filtration and combined with the previously obtained crystals. The combined crystals were dissolved in methanol-chloroform. After the solution was dried over anhydrous sodium sulfate, the solvent was removed by distillation in vacuo, so that 105.2 g (52%) of title compound (3) was obtained. After the filtrate was concentrated in vacuo, diisopropyl ether was added to the residue and stirred overnight. The precipitated crystals were separated by filtration to give 76.9 g (38%) of title compound (4).

(3)¹H-NMR (CDCl₃, δ):

0.98 (3H, d, J=7 Hz), 1.04 (3H, d, J=7 Hz), 1.35-1.59 (2H, m), 1.38 (9H, s), 1.70-1.87 (2H, m), 1.92-2.16 (3H, m), 3.20-3.33 (2H, m), 3.46 (1H, ddd, J=9 Hz, 9 Hz, 2 Hz), 4.33 (1H, d, J=2 Hz), 4.52-4.61 (2H, m), 4.94 (1H, d, J=9 Hz), 6.25 (1H, br-s), 7.58 (1H, d, J=6 Hz)

(4)¹H-NMR (CDCl₃, δ):

0.96 (3H, d, J=7 Hz), 1.02 (3H, d, J=7 Hz), 1.32-1.59 (2H, m), 1.44 (9H, s), 1.77-1.91 (2H, m), 1.99-2.20 (2H, m), 2.08-2.20 (1H, m), 3.21-3.34 (2H, m), 3.56 (1H, ddd, J=8 Hz, 8 Hz, 2 Hz), 4.29 (1H, dd, J=6 Hz, 2 Hz), 4.52 (1H, dd, J=11 Hz, 6 Hz), 4.75 (1H, d, J=6 Hz), 4.85 (1H, d, J=8 Hz), 6.06 (1H, br-s), 8.01 (1H, d, J=6 Hz)

(5) Production of (2R,3S)-3-amino-N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methylpentanamide

Four M hydrochloric acid/dioxane was added to (2R,3S)—N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methyl-3-[[(1,1-dimethylethoxy)carbonyl]amino]pentanamide (105.2 g, 294 mmol) and allowed to stand at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. After the residue was dissolved in water, the solution was allowed to pass through 180 ml of ion exchange resin (DOWEX, 1×4, 100-400 mesh). The eluate was concentrated in vacuo. The residue was dissolved in methanol-chloroform. After the solution was dried over anhydrous sodium sulfate, the solvent was removed by distillation in vacuo. Diisopropyl ether was added to the residue and stirred overnight. The precipitated crystals were separated by filtration to give 75.7 g (quantitative) of the title compound.

¹H-NMR (CDCl₃, δ):

1.01 (6H, d, J=7 Hz), 1.37-1.49 (1H, m), 1.56-1.68 (1H, m), 1.74-1.94 (3H, m), 1.99-2.09 (2H, m), 3.05 (1H, dd, J=7 Hz, 2 Hz), 3.22-3.37 (2H, m), 4.09 (1H, d, J=2 Hz), 4.57 (1H, dd, J=11 Hz, 7 Hz), 6.29 (1H, br-s), 7.82 (1H, d, J=7 Hz)

(6) Production of (2S,3S)-3-amino-N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methylpentanamide

Using (2S,3S)—N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methyl-3-[[(1,1-dimethylethoxy)carbonyl]amino]pentanamide (76.9 g, 215 mmol), the same procedure as in the production of (5) was performed to produce 40.8 g (74%) of the title compound.

¹H-NMR (CDCl₃, δ):

0.88 (3H, d, J=7 Hz), 0.94 (3H, d, J=7 Hz), 1.32-1.47 (1H, m), 1.52-1.60 (1H, m), 1.77-1.89 (2H, m), 1.98-2.08 (2H, m), 2.14-2.32 (1H, m), 2.66 (1H, dd, J=9 Hz, 4 Hz), 3.29-3.35 (2H, m), 3.78 (1H, d, J=9 Hz), 4.60 (1H, ddd, J=11 Hz, 6 Hz, 1 Hz), 5.97 (1H, br-s), 9.32 (1H, d, J=6 Hz)

Production Example 3 Production of N-[1-[[[(1S,2S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-2-hydroxy-1-(1-methylethyl)-3-oxopropyl]amino]carbonyl]cyclohexyl]-3-thiazolidinecarboxamide

Under ice cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (47 g, 247 mmol) was added to an N,N-dimethylformamide solution of 1-[(3-thiazolidinylcarbonyl)amino]cyclohexanecarboxylic acid (55 g, 215 mmol), (2S,3S)-3-amino-N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methylpentanamide (55 g, 215 mmol), triethylamine (109 g, 1.07 mol), and 1-hydroxybenzotriazole (36 g, 236 mmol). The liquid mixture was returned to room temperature and stirred overnight. The reaction mixture was diluted with dichloromethane. The dilution was washed with a 10% potassium hydrogen sulfate aqueous solution, a saturated sodium hydrogen carbonate aqueous solution, and brine. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation in vacuo, so that 78.8 g (74%) of the title compound was obtained.

¹H-NMR (CDCl₃, δ):

0.92 (3H, d, J=7 Hz), 0.99 (3H, d, J=7 Hz), 1.20-2.10 (17H, m), 3.06 (2H, t, J=6 Hz), 3.18-3.38 (2H, m), 3.71 (2H, t, J=6 Hz), 3.97 (1H, ddd, J=9 Hz, 9 Hz, 4 Hz), 4.20 (1H, dd, J=9 Hz, 4 Hz), 4.41-4.58 (3H, m), 4.74 (1H, s), 4.96 (1H, d, J=9 Hz), 6.16 (1H, t, J=6 Hz), 7.45 (1H, d, J=9 Hz), 7.64 (1H, d, J=6 Hz)

Example 1 Production of N-[1-[[[(1S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-1-(1-methylethyl)-2,3-dioxopropyl]amino]carbonyl]cyclohexyl]-3-thiazolidinecarboxamide (compound 1)

Under ice cooling, N,N-diisopropylethylamine (214 g, 1.66 mol) was added to a suspension of sulfur trioxide-pyridine (220 g, 1.38 mol) in 392 ml of dry dimethyl sulfoxide and 500 ml of dry dichloromethane and stirred at the same temperature for 15 minutes. At the same temperature, a dry dimethyl sulfoxide solution of N-[1-[[[(1S,2S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-2-hydroxy-1-(1-methylethyl)-3-oxopropyl]amino]carbonyl]cyclohexyl]-3-thiazolidinecarboxamide (68.8 g, 138 mmol) was added to the mixture and further stirred for 2 hours. The reaction mixture was poured into ice-water and then extracted with dichloromethane. The organic layer was washed with a 20% citric acid aqueous solution, a saturated sodium hydrogen carbonate aqueous solution, and brine. After the organic layer wad dried over anhydrous sodium sulfate, the solvent was removed by distillation in vacuo. The residue was purified by silica gel column chromatography to give 53 g (78%) of the title compound.

¹H-NMR (CDCl₃, δ):

0.84 (3H, d, J=7 Hz), 1.01 (3H, d, J=7 Hz), 1.25-2.21 (16H, m), 2.25-2.40 (1H, m), 3.08 (2H, t, J=6 Hz), 3.20-3.35 (2H, m), 3.71 (2H, t, J=6 Hz), 4.44 (1H, ddd, J=11 Hz, 6 Hz, 2 Hz), 4.45-4.60 (3H, m), 5.26 (1H, dd, J=8 Hz, 5 Hz), 6.41 (1H, t, J=6 Hz), 7.91 (1H, d, J=8 Hz), 8.17 (1H, d, J=6 Hz)

To determine the Rf value, measurement was performed by thin layer chromatography (TLC), and thin layer chromatography (TLC) analysis was performed under the conditions below. The Rf values shown in the experiments below were also obtained under the same conditions.

TLC: HPTLC plates RP-18F254s manufactured by Merck KGaA

Developing solvent: acetonitrile:water=7:3

Rf value: 0.59

Production Example 4 Production of N-[1-[[[(1S,2R)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-2-hydroxy-1-(1-methylethyl)-3-oxopropyl]amino]carbonyl]cyclohexyl]-1-pyrrolidinecarboxamide

Under ice cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (332 mg, 2.2 mmol) was added to a methylene chloride solution of 1-[(1-pyrrolidinylcarbonyl)amino]cyclohexanecarboxylic acid (482 mg, 2.0 mmol), (2R,3S)-3-amino-N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methylpentanamide hydrochloride (588 mg, 2.0 mmol), triethylamine (607 mg, 6.0 mol), and 1-hydroxybenzotriazole (322 mg, 2.1 mmol). The liquid mixture was returned to room temperature and stirred overnight. The reaction mixture was diluted with methylene chloride. The dilution was washed with a 10% potassium hydrogen sulfate aqueous solution, a saturated sodium hydrogen carbonate aqueous solution, and brine. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation in vacuo. Diisopropyl ether was added to the residue, and the resulting suspension was stirred overnight. The resulting solid was separated by filtration and then dried in vacuo to give 404 mg (42%) of the title compound.

¹H-NMR (CDCl₃, δ):

0.97 (3H, d, J=7 Hz), 1.01 (3H, d, J=7 Hz), 1.21-2.10 (20H, m), 2.26-2.40 (1H, m), 3.16-3.38 (2H, m), 3.23-3.42 (4H, m), 3.63 (1H, ddd, J=8 Hz, 8 Hz, 4 Hz), 4.26 (1H, dd, J=7 Hz, 4 Hz), 4.28 (1H, s), 4.48-4.62 (1H, m), 5.54 (1H, d, J=7 Hz), 5.90-6.02 (1H, m), 7.73 (1H, d, J=7 Hz), 7.76 (1H, d, J=8 Hz)

Example 2 Production of N-[1-[[[(1S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-1-(1-methylethyl)-2,3-dioxopropyl]amino]carbonyl]cyclohexyl]-1-pyrrolidinecarboxamide (compound 2)

To a dimethyl sulfoxide solution of N-[1-[[[(1S,2R)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-2-hydroxy-1-(1-methylethyl)-3-oxopropyl]amino]carbonyl]cyclohexyl]-1-pyrrolidinecarboxamide (404 mg, 0.84 mmol) was added 2-iodoxybenzoic acid (1.179 g, 4.2 mmol). After the mixture was stirred at room temperature for 2 hours, ethyl acetate and water were added to the reaction mixture. Sodium thiosulfate was then added to the mixture until a clear solution was obtained. After the organic and aqueous layers were allowed to separate, the organic layer was washed with saturated sodium bicarbonate water and brine. After the resulting organic layer was dried over sodium sulfate, the solvent was removed by distillation in vacuo. The resulting crude product was purified by silica gel column chromatography to give the title compound (59%).

¹H-NMR (CDCl₃, δ):

0.86 (3H, d, J=7 Hz), 1.02 (3H, d, J=7 Hz), 1.23-2.42 (21H, m), 3.18-3.42 (6H, m), 4.19 (1H, s), 4.40-4.53 (1H, m), 5.27 (1H, dd, J=8 Hz, 5 Hz), 6.13-6.29 (1H, m), 8.19 (1H, d, J=6 Hz), 8.35 (1H, d, J=8 Hz)

Rf value: 0.48

Production Example 5 Production of 1-[[[(2S)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid

(1) Production of 1-[[[(2S)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid benzyl ester

Under ice cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.33 g, 33 mmol) was added to a methylene chloride solution of 1-aminocyclohexanecarboxylic acid benzyl ester (7.00 g, 30 mmol), (2S)-tetrahydro-2-furancarboxylic acid (3.48 g, 30 mmol), and 1-hydroxybenzotriazole (4.82 g, 31.5 mmol). The liquid mixture was returned to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo, and the concentrate was diluted with ethyl acetate. The liquid mixture was washed with a 10% potassium hydrogen sulfate aqueous solution, a saturated sodium hydrogen carbonate aqueous solution, and brine. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation in vacuo, so that 8.88 g (89%) of the title compound was obtained.

¹H-NMR (CDCl₃, δ):

1.22-1.46 (3H, m), 1.52-1.69 (3H, m), 1.71-1.91 (4H, m), 1.97-2.06 (2H, m), 2.14-2.22 (2H, m), 3.85 (1H, q, J=8 Hz), 3.92 (1H, td, J=8 Hz, 6 Hz), 4.31 (1H, dd, J=8 Hz, 6 Hz), 5.09 (1H, d, J=13 Hz), 5.16 (1H, d, J=13 Hz), 6.84 (1H, s), 7.27-7.37 (5H, m)

(2) Production of 1-[[[(2S)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid

To a methanol solution of 1-[[[(2S)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid benzyl ester (8.88 g, 26.8 mmol) was added 10% palladium-carbon (500 mg) and stirred at room temperature under a hydrogen gas atmosphere overnight. The insoluble matter was removed by filtration, and the filtrate was concentrated in vacuo. Diisopropyl ether was added to the residue, and the resulting suspension was stirred overnight. The resulting crystals were separated by filtration and dried in vacuo to give 6.08 g (94%) of the title compound.

¹H-NMR (CDCl₃, δ):

1.28-1.43 (3H, m), 1.58-1.74 (3H, m), 1.84-1.99 (4H, m), 2.07-2.17 (3H, m), 2.26-2.35 (1H, m), 3.92 (1H, td, J=8 Hz, 7 Hz), 3.99 (1H, ddd, J=8 Hz, 7 Hz, 6 Hz), 4.41 (1H, dd, J=9 Hz, 6 Hz), 6.95 (1H, s)

Production Example 6 Production of (2S)—N-[1-[[[(1S,2S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-2-hydroxy-1-(1-methylethyl)-3-oxopropyl]amino]carbonyl]cyclohexyl]tetrahydro-2-furancarboxamide

(1) Production of 2-[(2S)-tetrahydro-2-furanyl]-3-oxa-1-azaspiro[4.5]dec-1-ene-4-one

To a methylene chloride solution of 1-[[[(2S)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid (362 mg, 1.5 mmol) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (307 mg, 1.6 mmol) and stirred at room temperature for 4 hours. The reaction mixture was then concentrated in vacuo. Ethyl acetate was added to the residue, and the mixture was washed sequentially with water, a 10% potassium hydrogen sulfate aqueous solution, a saturated sodium hydrogen carbonate aqueous solution, and brine. After drying over anhydrous sodium sulfate, the solvent was removed by distillation in vacuo, so that 323 mg (96%) of the title compound was obtained.

¹H-NMR (CDCl₃, δ):

1.45-1.57 (1H, m), 1.58-1.79 (9H, m), 1.96-2.17 (3H, m), 2.24-2.32 (1H, m), 3.94 (1H, td, J=8 Hz, 6 Hz), 4.04 (1H, td, J=8 Hz, 7 Hz), 4.70 (1H, J=8 Hz, 6 Hz)

(2) Production of (2S)—N-[1-[[[(1S,2S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-2-hydroxy-1-(1-methylethyl)-3-oxopropyl]amino]carbonyl]cyclohexyl]tetrahydro-2-furancarboxamide

Five ml of an N,N-dimethylformamide solution of 2-[(2S)-tetrahydro-2-furanyl]-3-oxa-1-azaspiro[4.5]dec-1-ene-4-one (323 mg, 1.45 mmol) and (2S,3S)-3-amino-N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methylpentanamide (386 mg, 1.5 mmol) was stirred at 80° C. overnight. After the reaction mixture was concentrated in vacuo, the concentrate was purified by silica gel column chromatography to give 610 mg (88%) of the title compound.

¹H-NMR (CDCl₃, δ):

0.90 (3H, d, J=7 Hz), 0.96 (3H, d, J=7 Hz), 1.22-2.09 (19H, m), 2.17-2.30 (2H, m), 3.22-3.30 (2H, m), 3.93 (1H, q, J=8 Hz), 4.00-4.08 (1H, m), 4.02 (1H, q, J=8 Hz), 4.17 (1H, d, J=3 Hz), 4.41 (1H, dd, J=8 Hz, 6 Hz), 4.49 (1H, dd, J=10 Hz, 6 Hz), 6.49 (1H, br-s), 7.05 (1H, s), 7.19 (1H, d, J=8 Hz), 7.78 (1H, d, J=6 Hz)

Example 3 Production of (2S)—N-[1-[[[(1S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-1-(1-methylethyl)-2,3-dioxopropyl]amino]carbonyl]cyclohexyl]tetrahydro-2-furancarboxamide (enantiomer of compound 3)

Under ice cooling, N,N-diisopropylethylamine (985 mg, 7.62 mmol) was added to a suspension of sulfur trioxide-pyridine (1.21 g, 7.62 mmol) in 10 ml of dry dimethyl sulfoxide and 5 ml of dry dichloromethane and stirred at the same temperature for 15 minutes. At the same temperature, a dry dimethyl sulfoxide solution of (2S)—N-[1-[[[(1S,2S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-2-hydroxy-1-(1-methylethyl)-3-oxopropyl]amino]carbonyl]cyclohexyl]tetrahydro-2-furancarboxamide (610 mg, 1.27 mmol) was added to the mixture and further stirred for 2 hours. The reaction mixture was poured into ice-water and then extracted with methylene chloride. The organic layer was washed with a 20% citric acid aqueous solution, a saturated sodium hydrogen carbonate aqueous solution, and brine. After the organic layer wad dried over anhydrous sodium sulfate, the solvent was removed by distillation in vacuo. The residue was purified by silica gel column chromatography to give 359 mg (59%) of the title compound.

¹H-NMR (CDCl₃, δ):

0.83 (3H, d, J=7 Hz), 1.02 (3H, d, J=7 Hz), 1.23-1.71 (8H, m), 1.78-2.23 (10H, m), 2.28-2.40 (3H, m), 3.22-3.35 (2H, m), 3.92 (1H, q, J=7 Hz), 4.02 (1H, q, J=7 Hz), 4.38 (1H, dd, J=8 Hz, 6 Hz), 4.46 (1H, dd, J=10 Hz, 6 Hz), 5.25 (1H, dd, J=8 Hz, 5 Hz), 5.98 (1H, t, J=7 Hz), 6.76 (1H, s), 7.95 (1H, d, J=8 Hz), 8.17 (1H, d, J=6 Hz) Rf value: 0.60

Production Example 7 Production of 1-[[[(2R)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid

(1) Production of 1-[[[(2R)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid benzyl ester

Using (2R)-tetrahydro-3-furancarboxylic acid (3.48 g, 30 mmol), 9.03 g (91%) of the title compound was obtained by the same procedure as in Production Example 5 (1).

¹H-NMR (CDCl₃, δ):

1.22-1.46 (3H, m), 1.52-1.70 (3H, m), 1.71-1.93 (4H, m), 1.97-2.05 (2H, m), 2.14-2.22 (2H, m), 3.85 (1H, q, J=8 Hz), 3.92 (1H, td, J=8 Hz, 7 Hz), 4.31 (1H, dd, J=8 Hz, 6 Hz), 5.09 (1H, d, J=13 Hz), 5.16 (1H, d, J=13 Hz), 6.84 (1H, s), 7.27-7.37 (5H, m)

(2) Production of 1-[[[(2R)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid

Using 1-[[[(2R)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid benzyl ester (9.03 g, 27.2 mmol), 5.92 g (82%) of the title compound was obtained by the same procedure as in Production Example 5 (2).

¹H-NMR (CDCl₃, δ):

1.27-1.43 (3H, m), 1.59-1.75 (3H, m), 1.84-2.00 (4H, m), 2.06-2.18 (3H, m), 2.28-2.36 (1H, m), 3.93 (1H, td, J=8 Hz, 7 Hz), 4.00 (1H, ddd, J=8 Hz, 7 Hz, 6 Hz), 4.41 (1H, dd, J=9 Hz, 6 Hz), 6.95 (1H, s)

Production Example 8 Production of (2R)—N-[1-[[[(1S,2S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-2-hydroxy-1-(1-methylethyl)-3-oxopropyl]amino]carbonyl]cyclohexyl]tetrahydro-2-furancarboxamide

Using 1-[[[(2R)-tetrahydro-2-furanyl]carbonyl]amino]cyclohexanecarboxylic acid (362 mg, 1.5 mmol), 302 mg (90%) of 2-[(2R)-tetrahydro-2-furanyl]-3-oxa-1-azaspiro[4.5]dec-1-ene-4-one was obtained by the same procedure as in Production Example 6 ((1) and (2)). To the product was added 5 ml of an N,N-dimethylformamide solution of (2S,3S)-3-amino-N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methylpentanamide (386 mg, 1.5 mmol) and stirred at 80° C. overnight. After the reaction mixture was concentrated in vacuo, the concentrate was purified by silica gel column chromatography to give 421 mg (65%) of the title compound.

¹H-NMR (CDCl₃, δ):

0.92 (3H, d, J=7 Hz), 0.99 (3H, d, J=7 Hz), 1.25-2.15 (20H, m), 2.22-2.32 (1H, m), 3.20-3.34 (2H, m), 3.91 (1H, q, J=8 Hz), 3.95 (1H, ddd, J=8 Hz, 8 Hz, 3 Hz), 4.01 (1H, q, J=8 Hz), 4.25 (1H, d, J=3 Hz), 4.33 (1H, dd, J=8 Hz, 6 Hz), 4.48 (1H, dd, J=10 Hz, 6 Hz), 6.10 (1H, t, J=7 Hz), 6.95 (1H, s), 7.39 (1H, d, J=8 Hz), 7.83 (1H, d, J=6 Hz)

Example 4 Production of (2R)—N-[1-[[[(1S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-1-(1-methylethyl)-2,3-dioxopropyl]amino]carbonyl]cyclohexyl]tetrahydro-2-furancarboxamide (compound 3)

Using (2R)—N-[1-[[[(1S,2S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-2-hydroxy-1-(1-methylethyl)-3-oxopropyl]amino]carbonyl]cyclohexyl]tetrahydro-2-furancarboxamide (610 mg, 1.27 mmol), 320 mg (76%) of the title compound was obtained by the same procedure as in Example 3 described above.

¹H-NMR (CDCl₃, δ):

0.82 (3H, d, J=7 Hz), 1.01 (3H, d, J=7 Hz), 1.23-1.70 (8H, m), 1.78-2.18 (10H, m), 2.19-2.40 (3H, m), 3.21-3.35 (2H, m), 3.92 (1H, q, J=7 Hz), 4.00 (1H, q, J=7 Hz), 4.39 (1H, dd, J=8 Hz, 6 Hz), 4.46 (1H, dd, J=10 Hz, 6 Hz), 5.29 (1H, dd, J=8 Hz, 5 Hz), 5.94 (1H, t, J=8 Hz), 6.77 (1H, s), 7.79 (1H, d, J=8 Hz), 8.18 (1H, d, J=6 Hz)

Rf value: 0.60

Test Examples

As described below, cathepsin K inhibitory activity and bone resorption inhibitory activity were measured according to the method shown in JP 2000-204071 A. Comparative compounds 1 to 15 shown below are the top 15 compounds showing good results among the cyclic amide derivative compounds that are disclosed as having high bone resorption inhibitory activity in low-calcium diet mice in JP 2000-204071 A (Patent Literature 1).

Comparative compound 1: the compound of Example 120 in Patent Literature 1

Comparative compound 2: the compound of Example 5 in Patent Literature 1

Comparative compound 3: the compound of Example 140 in Patent Literature 1

Comparative compound 4: the compound of Example 121 in Patent Literature 1

Comparative compound 5: the compound of Example 82 in Patent Literature 1

Comparative compound 6: the compound of Example 97 in Patent Literature 1

Comparative compound 7: the compound of Example 92 in Patent Literature 1

Comparative compound 8: the compound of Example 33 in Patent Literature 1

Comparative compound 9: the compound of Example 131 in Patent Literature 1

Comparative compound 10: the compound of Example 64 in Patent Literature 1

Comparative compound 11: the compound of Example 34 in Patent Literature 1

Comparative compound 12: the compound of Example 81 in Patent Literature 1

Comparative compound 13: the compound of Example 6 in Patent Literature 1

Comparative compound 14: the compound of Example 135 in Patent Literature 1

Comparative compound 15: the compound of Example 27 in Patent Literature 1

As to cathepsin K inhibitory activity, comparative compounds 1 to 15 and compounds according to the present invention (compounds 1, 2, and 3 shown below are the compounds obtained in Examples 1, 2, and 4, respectively) were measured for IC₅₀ value (50% inhibitory concentration). As to bone resorption inhibitory activity, only the compounds of the present invention were subjected to the measurement, while the data shown in JP 2000-204071 were used with respect to comparative compounds 1 to 15.

As to CYP3A4 inhibitory activity, comparative compounds 1 to 15 and the compounds of the present invention were each measured for DI (direct inhibition) and MBI (mechanism based inhibition), and the IC₅₀ value for DI and MBI was each calculated.

On the basis of these data, calculations were made to determine the ratio (CYP/CatK) between the IC₅₀ values for CYP3A4 inhibitory activity (MBI) and the IC₅₀ values for cathepsin K inhibitory activity with respect to the comparative compounds and the compounds of the present invention, and the selectivity for the target enzyme cathepsin K was evaluated.

Test Example 1 Measurement of Cathepsin K Inhibitory Activity

Cathepsin K was prepared as follows. The proenzyme of cathepsin K was produced in cell culture media using a baculovirus expression system in Sf21 insect cells and then incubated at 40° C. for 1 hour to form the active enzyme (Tezuka et al., J. Biol. Chem., 269, 1106-1109 (1994)). The activity of cathepsin K was measured from the decomposition of the fluorescent substrate Z-Gly-Pro-Arg-MCA (3208-v from PEPTIDE INSTITUTE, INC.) according to the method of Aibe et al. (Aibe et al., Biol. Pharm. Bull., 19, 1026-1031 (1996)). Specifically, the decomposition of 20 μM Z-Gly-Pro-Arg-MCA by cathepsin K was measured in 100 mM potassium sodium phosphate, 1 mM EDTA, 8 mM Cysteine, pH 6.0. The reaction was performed at 37° C. for 30 minutes and then quenched by the addition of 2×10⁻⁵ M of calpeptin. After the reaction was quenched, the intensity of fluorescence was measured at an excitation wavelength of 355 nm and a measurement wavelength of 460 nm.

As to the measurement results, Tables 3 and 4 show the IC₅₀ values (nmol/L) of the comparative compounds and the compounds of the present invention, respectively, together with the results of other test examples.

Test Example 2 Measurement of Bone Resorption Inhibitory Activity

The measurement was performed by the same method as described in JP 2000-204071 A (Patent Literature 1). Specifically, male mice (23 to 25 g weight, 8 mice per group) were fed with low-calcium diet (0.1% calcium diet) for 7 days. After overnight fasting, the compound of the present invention was orally administered to the mice at 100 mg/kg weight, and 4 hours after the administration, the calcium concentration of the serum was measured by the methyl xylenol blue method (Biochem Biophys Res Commun., 125, 441-447 (1984), FEBS Lett., 321 (2-3), 247-250 (1993)). The rate (%) of decrease in serum calcium was determined by comparison with the control group.

Tables 3 and 4 show the results of the measurement of the comparative compounds and the compounds of the present invention, respectively, together with the results of other tests. It should be noted that the data of the rate (%) of decrease in serum calcium as to comparative compounds 1 to 15 are the values shown in JP 2000-204071 A (Patent Literature 1).

Test Example 3 Measurement of CYP3A4 Inhibitory Activity

The measurement of CYP3A4 inhibitory activity was performed with reference to the method of Newton et al. (Drug Metab. Dispos. 23, 154-158 (1995)) and the method described in JP 2007-236327 A.

A reaction mixture was prepared by mixing the compound of the present invention with midazolam as a typical substrate for CYP3A4 (see Food and Drug Administration (FDA) Guidance for Industry Drug Interaction Studies—Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations. FDA web site [online], www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf), coenzyme NADPH-generating system, human hepatic microsomes, and a phosphate buffer. The reaction mixture was incubated at 37° C. for 10 minutes. Table 1 below shows the solutions used in the preparation of the coenzyme NADPH-generating system solution.

TABLE 1 Prepared Compound Name Solvent Concentration β-Nicotinamide adenine Phosphate Buffer 13 mmol/L dinucleotide phosphate (pH 7 .4) (β-NADP⁺) glucose-6-phosphate Phosphate Buffer 33 mmol/L (G-6-P) (pH 7.4) glucose-6-phosphate Phosphate Buffer 10 U/mL dehydrogenase (pH 7.4) (G-6-P DH(Y)) MgCl₂ Phosphate Buffer 33 mmol/L (pH 7.4)

The coenzyme NADPH-generating system solution was prepared by mixing the materials shown in Table 1: the 13 mmol/L β-NADP⁺ solution, the 33 mmol/L G-6-P solution, the solution of 10 U/mL G6PDH (Y) (manufactured by Oriental Yeast Co., Ltd.), and the 33 mmol/L MgCl₂ solution in a ratio of 1:1:0.4:1 (v:v:v:v). Table 2 below shows the composition of the reaction mixture used in the measurement of CYP3A4 inhibitory activity. The final concentrations of the compounds of the present invention and the comparative compounds were set at the levels considered to be necessary for the calculation of the IC₅₀ values based on the results of the measurement performed at an arbitrary concentration in advance.

TABLE 2 Added Solution Amount (μL) Final Concentration Inventive Compound or 5 It was set at the Comparative Compound level necessary for the calculation of the IC₅₀ value. Midazolam Solution 10 1000 nmol/L 0.1M Phosphate 265 — Buffer (pH 7.4) Coenzyme NADPH- 170 β-NADP⁺ 1.3 mmol/L Generating System G-6-P 3.3 mmol/L Solution G-6-P DH (Y) 0.4 U/mL MgCl₂ 3.3 mmol/L Diluted Microsomes 50 0.1 mg protein/mL

After the incubation, the reaction was quenched by the addition of an acetonitrile solution to the reaction mixture. The amount of 1′-hydroxymidazolam produced (the metabolite produced from midazolam by CYP3A4) was measured in the quenched sample with a high-performance liquid chromatography tandem mass spectrometer (LC-MS/MS). Each IC₅₀ value for DI (direct inhibition) was determined from the amount of the produced 1′-hydroxymidazolam and the final concentration of the compound of the present invention or the comparative compound in the reaction mixture.

MBI (mechanism based inhibition) was evaluated as follows. After the reaction mixture not containing midazolam (but containing the compound of the present invention or the comparative compound, the coenzyme NADPH-generating system, the human hepatic microsomes, and the phosphate buffer) was pre-incubated at 37° C. for 30 minutes, midazolam was added to the reaction mixture. The reaction mixture was then incubated at 37° C. for 10 minutes. Subsequently, the reaction was quenched by the addition of an acetonitrile solution to the reaction mixture. The amount of 1′-hydroxymidazolam produced was measured in the quenched sample with an LC-MS/MS. As in the case of DI, each IC₅₀ value for MBI was determined from the amount of the produced 1′-hydroxymidazolam and the final concentration of the compound of the present invention or the comparative compound in the reaction mixture.

Tables 3 and 4 show the results of the measurement of the comparative compounds and the compounds of the present invention, respectively, together with the results of other tests.

TABLE 3 Rate of Decrease CatK CYP3A4 in Inhibitory Inhibitory IC₅₀ Comparative Serum Ca IC₅₀ (μmol/L) CYP/ Compound (%) (nmol/L) DI MBI CatK 1 5.39 16 11.7 3.36 207 2 4.71 13 9.31 1.53 122 3 4.50 3.4 0.180 0.0373 11 4 4.48 7.4 12.6 2.16 291 5 4.38 26 14.0 4.59 179 6 4.33 20 8.28 2.07 103 7 4.08 23 23.7 4.41 193 8 4.07 7.8 15.5 2.57 328 9 3.97 39 0.723 0.0924 2 10 3.60 16 15.5 3.85 246 11 3.50 5.4 10.8 2.07 384 12 3.50 3.6 5.23 0.985 274 13 3.46 6 2.78 2.23 370 14 3.37 4.8 0.994 0.152 31 15 3.26 12 16.0 4.97 401

TABLE 4 Rate of CatK Decrease in inhibitory CYP3A inhibitory Inventive Serum Ca IC₅₀ IC₅₀ (μmol/L) Compound (%) (nmol/L) DI MBI CYP/CatK Compound 1 4.8 0.79 43.5 44.4 56555 Compound 2 4.5 1.4 101 73.1 52214 Compound 3 4.5 3.4 208 137 40294

These results show that all the comparative compounds have an IC₅₀ value (MBI) of less than 10 μM for CYP3A4 inhibition whereas the compounds of the present invention have an IC₅₀ value of more than 40 μM for CYP3A4 inhibition.

Therefore, according to the above-mentioned classification of the intensity of CYP3A4 inhibition, all the comparative compounds are determined to have at least a medium level of CYP3A4 inhibitory activity, whereas the compounds of the present invention are determined to have a low level of CYP3A4 inhibitory activity.

The enzyme selectivity (CYP/CatK) of the compounds of the present invention is calculated to be a value of more than 40,000 whereas that of the comparative compounds is calculated to be a value of less than about 400. 

1. An α-oxoacylaminocaprolactam of formula (I):

wherein X is N or CH, Y is O or CH₂, and Z is S or CH₂.
 2. The α-oxoacylaminocaprolactam according to claim 1, wherein in formula (I), X is N, Y is CH₂, and Z is S.
 3. The α-oxoacylaminocaprolactam according to claim 1, wherein in formula (I), X is N, Y is CH₂, and Z is CH₂.
 4. The α-oxoacylaminocaprolactam according to claim 1, wherein in formula (I), X is CH, Y is O, and Z is CH₂.
 5. A pharmaceutical composition comprising the α-oxoacylaminocaprolactam according to claim 1 and a pharmaceutically acceptable carrier.
 6. The pharmaceutical composition according to claim 5, which is a medicament for treating or preventing a disease caused by accelerated bone resorption.
 7. The pharmaceutical composition according to claim 6, wherein the disease caused by accelerated bone resorption is osteoporosis, hypercalcemia, Paget's disease, bone resorption disease, osteogenesis imperfecta, osteoarthritis, rheumatoid arthritis, arthritis, Klinefelter syndrome, hereditary hyperphosphatasia, Charcot neuroarthropathy, mastocytosis, Gaucher disease, cancer metastasis, or multiple myeloma. 